Activators of autophagic flux and phospholipase d and clearance of protein aggregates including tau and treatment of proteinopathies

ABSTRACT

The present application discloses compounds which are activators of autophagic flux and pharmaceutical compositions comprising said activators. It further discloses use of said compounds and pharmaceutical compositions in the treatment of neurodegenerative diseases, particularly proteinopathies and tauopathies such as Alzheimer&#39;s disease. It further discloses methods of enhancing autophagic flux.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims benefit to U.S. Provisional Application Ser. No. 62/237,342, filed Oct. 5, 2015. The entire contents of the above application are incorporated by reference as if recited in full herein.

FIELD OF THE DISCLOSURE

The present disclosure relates to compounds which are activators of autophagic flux and pharmaceutical compositions comprising said compounds. It further relates to use of said compounds in the treatment of neurodegenerative diseases, particularly Alzheimer's disease.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) affects approximately five million Americans and this number is predicted to triple by 2050. At present, there are no therapies to treat Alzheimer's or other related tauopathies. While clinical trials using immunotherapy targeting amyloid beta (Aβ) have had limited success, this in only subset of those afflicted with AD or other neurodegenerative diseases. Moreover, there are no therapies targeting other proteinopathies, including tau, the other major neuropathological component of AD. AD accounts for most of the dementias afflicting individuals over 65 and is estimated to cost $226 billion in healthcare, long-term care, and hospice for people with AD and other dementias annually. This extensive economic and societal burden does not account for lost income of many at-home primary caregivers including spouses and other family members.

Enhancing autophagy has been shown to have therapeutic potential in the treatment of Alzheimer's disease. Autophagic flux (including the fusion of autophagosomes to lysosomes) is a novel regulator of autophagy as it leads to the clearance of protein aggregates and reversal of pathophysiological decline. Therefore, there exists an ongoing need for promoters of autophagic flux and the clearance of autophagosomes bearing proteinopathies.

SUMMARY OF THE INVENTION

In some embodiments, compounds including pharmaceutically acceptable salts thereof, which are disclosed herein, are provided.

In some embodiments a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof. In other embodiments, methods of making the compounds and pharmaceutical compositions are also provided in, e.g., the Examples provided below.

In some embodiments a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided.

In some embodiments a method of enhancing autophagic flux is provided. This method comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.

These and other aspects of the invention are further disclosed in the detailed description and examples which follow.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.

FIG. 1 is a graph showing a photodiode array (PDA) spectrum of WHYKD8 in mouse brain.

FIG. 2 shows Western blots of LC3-II levels in primary cortical neurons following a 6 hour treatment with WHYKD1 (±BafA1) or WHYKD5.

FIG. 3 shows Western blots of LC3-II, tau, and p62 levels in organotypic slice cultures following a 6 hour treatment with WHYKD1 (top) or WHYKD3, WHYKD5, WHYKD8, WHYKD9, or WHYKD12 (bottom).

FIG. 4 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (10 μM), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol. C=Control, 12=WHYKD12, 15=WHYKD15, 19=WHYKD19, 5=WHYKD5, 8=WHYKD8, Fipi=a noncompetitive inhibitor of PLD activity.

FIG. 5 is a bar graph showing the activation of phospholipase D (PLD) by the WHYKD series compounds (1 μM), and their ability to convert phospholipids to phosphatidylethanols in the presence of ethanol.

DETAILED DESCRIPTION OF THE INVENTION

Although macroautophagy is known to be an essential degradative process whereby autophagosomes mediate the engulfment and delivery of cytoplasmic components into lysosomes, the lipid changes underlying autophagosomal membrane dynamics are undetermined. The inventors have previously shown that PLD1, which is primarily associated with the endosomal system, partially relocalizes to the outer membrane of autophagosome-like structures upon nutrient starvation (Dall'Armi, 2010). The localization of PLD1, as well as the starvation-induced increase in PLD activity, are altered by wortmannin, a phosphatidylinositol 3-kinase inhibitor, suggesting PLD1 may act downstream of Vps34. Pharmacological inhibition of PLD and genetic ablation of PLD1 in mouse cells decreased the starvation-induced expansion of LC3-positive compartments, consistent with a role of PLD1 in the regulation of autophagy. Furthermore, inhibition of PLD results in higher levels of tau and p62 aggregates in organotypic brain slices. These in vitro and in vivo findings establish a role for PLD1 in autophagy.

In some embodiments, a compound is provided having the formula (II):

wherein Y¹ and Y² are independently selected from the group consisting of CH and wherein X is selected from the group consisting of H, halide, and aryl; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In one embodiment the compound is:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In another embodiment the compound is:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (III):

wherein Y¹ is CH; wherein Y² is N; wherein X is halide; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (IV):

wherein X is halide; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (V):

wherein X is H; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (VI):

wherein X is H; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (VII):

wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (VIII):

wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (IX):

wherein Y³ is CH or N; wherein R² is optionally substituted (2-aminoethyl)aryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (X):

wherein Y³ is CH; wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (XI):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (XII):

wherein Y⁴ is CH or N; wherein R³ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (XIII):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (XIV):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments, a compound is provided having the formula (XV):

wherein X is H or halide; wherein Z¹ is O; wherein R⁴ is selected from the group consisting of H, optionally substituted alkyl, Et, CF₃, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and

In some embodiments, the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In one embodiment the compound is

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.

In some embodiments a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof.

In some embodiments a method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound or pharmaceutical composition disclosed herein is provided. In some embodiments the neurodegenerative disease is a proteinopathy. Proteinopathies include, but are not limited to, Parkinson's disease, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Huntington's disease, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), inclusion body myopathy (IBM), Paget's disease of bone (PDB), cerebral β-amyloid angiopathy, prion diseases, familial dementia, CADASIL, amyloidosis, Alexander disease, seipinopathies, type II diabetes, pulmonary alveolar proteinosis, cataracts, cystic fibrosis and sickle cell disease. In some aspects of this embodiment, the proteinopathy is a tauopathy. Tauopothies include but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy, chronic traumatic encephalopathy (CTE), frontotemporal dementia (FTD), Lytico-Bodig disease, subacute sclerosing panencephalitis, ganglioglioma, gangliocytoma, and argyrophilic grain disease. In a preferred embodiment, the neurodegenerative disease is Alzheimer's disease.

In some embodiments a method of enhancing autophagic flux is provided. This method comprises providing to a cell or a protein aggregate an effective amount of a compound or pharmaceutical composition disclosed herein.

The embodiments described in this disclosure can be combined in various ways. Any aspect or feature that is described for one embodiment can be incorporated into any other embodiment mentioned in this disclosure. While various novel features of the inventive principles have been shown, described and pointed out as applied to particular embodiments thereof, it should be understood that various omissions and substitutions and changes may be made by those skilled in the art without departing from the spirit of this disclosure. Those skilled in the art will appreciate that the inventive principles can be practiced in other than the described embodiments, which are presented for purposes of illustration and not limitation.

EXAMPLES

The following examples are provided to further illustrate certain aspects of the present invention. These examples are illustrative only and are not intended to limit the scope of the invention in any way.

Example 1 Example Synthetic Schemes

Scheme 1 shows the synthesis of compounds of the formula:

e.g., compounds of formula (II) and formula (III).

Scheme 2 shows preparation of 1-chloro-7-fluoroisoquinoline.

Scheme 3 shows the synthesis of compounds of the formula:

e.g., compounds of formula (IV), formula (V), formula (VI), formula (VII), and formula (VIII).

Scheme 4 shows the synthesis of compounds of the formula:

e.g., compounds of formula (XII), and formula (XIII).

Scheme 5 shows the synthesis of compounds of the formula:

e.g., compounds of formula (IX), formula (X), and formula (XI).

Scheme 6 shows the synthesis of compounds of the formula:

e.g., compounds of formula (XIV).

Example 2 Activators of Autophagic Flux and Phospholipase D

The WHYKD series of compounds were synthesized for optimal brain penetrance based on the molecular weight (MW) and partition coefficient (log P), according to Lipinski's Rule for CNS penetrance: MW≤400, log P≤5.

Activators according to the formula:

were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 1 below.

TABLE 1 PROJECT STRUCTURE ID M.W. log P X Y¹ Y² R¹

WHYKD3  323.17 3.85 Br N N thioheteroaryl

WHYKD4  369.44 5.69 aryl N N Thioheteroaryl

WHYKD5  262.27 3.18 F N N Thioheteroaryl

WHYKD6  244.48 3.02 H N N thioheteroaryl

WHYKD7  278.72 3.58 Cl N N thioheteroaryl

WHYKD8  299.76 3.91 Cl N N (2- aminoethyl)aryl

WHYKD9  182.58 2.58 F N N Cl

WHYKD10 243.29 2.9  H N CH thioheteroaryl

WHYKD11 261.28 3.06 F N CH thioheteroaryl

WHYKD12 262.35 4.35 F N N thiocycloalkyl

WHYKD13 316.44 5.21 F N N thiocycloalkyl

WHYKD14 314.42 4.66 F N N thiocycloalkyl

WHYKD15 248.32 3.96 F N N thiocycloalkyl

WHYKD16 274.36 4.19 F N N thiocycloalkyl

WHYKD17 357.49 4.09 F N N thiocycloalkyl

WHYKD18 386.48 4.41 F N N thiocycloalkyl

WHYKD19 264.32 2.63 F N N thiocycloalkyl

WHYKD20 296.36 4.8  F N N thioaryl

Activators according to the formula:

were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 2 below.

TABLE 2 PROJECT STRUCTURE ID M.W. log P Y³ R²

WHYKD21 272.33 3.36 N (2- aminoethyl)aryl

WHYKD23 271.34 3.66 CH (2- aminoethyl)aryl Activators according to the formula:

were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 3 below.

TABLE 3 PROJECT STRUCTURE ID M.W. log P Y⁴ R³

WHYKD1 251.29 2.56 N thioheteroaryl

WHYKD2 272.33 2.89 N (2- aminoethyl)aryl

WHYKD22 271.34 3.34 CH (2- aminoethyl)aryl

Activators according to the formula:

were synthesized according to the schemes above. Molecular weights and log P were calculated. Results are shown in Table 4 below.

TABLE 4 PROJECT log STRUCTURE ID M.W. P X Y¹ Y² R⁴ Z¹

WHYKD24 164.14 1.02 F N N H O

Example 3 Design of Derivatives

Several series of derivatives were synthesized based on the following lead compounds:

In addition to log P, the topological polar surface area (tPSA), C Log P (log P calculated by group contribution method), and Log S (solubility) were calculated. Results are shown in the Tables below.

TABLE 5 Modifications to the core and side chain (Series 1) STRUCTURE log P tPSA CLogP LogS

3.35 52.68 2.65154 −3.235

3.12 61.47 2.34241 −3.295

2.94 40.32 1.83259 −4.663

3.19 27.96 3.25375 −3.864

4.14 12.36 4.64041 −4.354

2.71 49.11 2.01759 −4.354

2.95 36.75 3.23654 −3.554

2.8  21.59 2.80041 −3.813

4.56 12.36 5.19941 −4.832

TABLE 6 Modifications to the core and side chain (Series 2) STRUCTURE log P tPSA CLogP LogS

2.31 77.4 0.803829 −1.704

2.07 86.19 0.539011 −1.765

1.9 65.04 −0.0366305 −3.133

1.66 73.83 0.148224 −2.824

2.14 52.68 1.40054 −2.334

1.91 61.47 1.38428 −2.024

3.09 37.08 2.83701 −2.823

3.51 37.08 3.39601 −3.301

1.76 46.31 0.997011 −2.283

TABLE 7 Modifications to the core and side chain (Series 3) STRUCTURE log P tPSA CLogP LogS

2.89 77.4 0.647513 −1.626

2.65 86.19 0.382662 −1.686

2.48 65.04 −0.192932 −3.117

2.25 73.83 −0.00808129 −2.806

2.73 52.68 1.24423 −2.303

2.49 61.47 1.22796 −1.992

3.68 37.08 2.68066 −2.893

4.09 37.08 3.23966 −3.372

2.34 46.31 0.840662 −2.256

TABLE 8 Modifications to the core and side chain (Series 4) STRUCTURE log P tPSA CLogP LogS

1.68 77.4 0.647513 −1.441

1.45 86.19 0.382662 −1.501

1.28 65.04 −0.192932 −2.932

1.04 73.83 −0.00808129 −2.621

1.52 52.68 1.24423 −2.119

1.28 61.47 1.22796 −1.808

2.47 37.08 2.68066 −2.704

2.89 37.08 3.23966 −3.183

1.13 46.31 0.840662 −2.071

TABLE 9 Modifications to the core and side chain (Series 5) STRUCTURE log P tPSA CLogP LogS

1.68 77.4 0.647513 −1.466

1.45 86.19 0.382662 −1.526

1.28 65.04 −0.192932 −2.957

1.04 73.83 −0.00808129 −2.646

1.52 52.68 1.24423 −2.144

1.28 61.47 1.22796 −1.832

2.47 37.08 2.68066 −2.733

2.89 37.08 3.23966 −3.212

1.13 46.31 0.840662 −2.096

TABLE 10 Modifications to the core and side chain (Series 6) STRUCTURE log P tPSA CLogP LogS

2.11 77.4 0.857513 −1.525

1.87 86.19 0.592663 −1.585

1.7 65.04 0.0170677 −3.017

1.46 73.83 0.201919 −2.705

1.94 52.68 1.45423 −2.203

1.71 61.47 1.43796 −1.892

2.89 37.08 2.89066 −2.787

3.31 37.08 3.44966 −3.266

1.55 46.31 1.05066 −2.155

TABLE 11 Modifications to the core and side chain (Series 7) STRUCTURE log P tPSA CLogP LogS

1.63 74.27 1.1096 −1.275

1.4 83.06 0.834 −1.333

1.23 61.91 0.272969 −2.704

0.99 70.7 0.457768 −2.391

1.47 49.55 1.70682 −1.904

1.24 58.34 1.69005 −1.592

2.42 33.95 3.132 −2.403

2.84 33.95 3.691 −2.883

1.08 43.18 1.292 −1.864

TABLE 12 Modifications to the core and side chain (Series 8) STRUCTURE log P tPSA CLogP LogS

1.96 74.27 0.8996 −1.745

1.72 83.06 0.624 −1.803

1.55 61.91 0.0629689 −3.174

1.31 70.7 0.247768 −2.862

1.79 49.55 1.49682 −2.374

1.56 58.34 1.48005 −2.062

2.74 33.95 2.922 −2.874

3.16 33.95 3.481 −3.353

1.4 43.18 1.082 −2.335

TABLE 13 Modifications to the core and side chain (Series 9) STRUCTURE log P tPSA CLogP LogS

3.0 65.04 1.74907 −2.051

2.76 73.83 1.47586 −2.109

2.59 52.68 0.911314 −3.542

2.36 61.47 1.09641 −3.23

2.84 40.32 2.34546 −2.728

2.6 49.11 2.32952 −2.416

3.79 24.72 3.77386 −3.323

4.2 24.72 4.33286 −3.802

2.45 33.95 1.93386 −2.687

TABLE 14 Modifications to the core and side chain (Series 10) STRUCTURE log P tPSA CLogP LogS

2.94 65.04 1.53907 −2.188

2.71 73.83 1.26586 −2.247

2.54 52.68 0.701314 −3.68

2.3 61.47 0.886405 −3.367

2.78 40.32 2.13546 −2.866

2.55 49.11 2.11952 −2.554

3.73 24.72 3.56386 −3.468

4.15 24.72 4.12286 −3.947

2.39 33.95 1.72386 −2.824

TABLE 15 Quinazolinones (Series 11) STRUCTURE log P tPSA CLogP LogS

1.02 41.46 0.506065 −1.702

1.42 41.46 1.07606 −2.152

1.69 41.46 1.22606 −2.273

0.86 41.46 0.305 −1.452

Example 4 Detection and Results of WHYKD Compounds

A photodiode array (PDA) was used to detect WHYKD8 in mouse brain (FIG. 1). The sample was readily detected with a discrete peak based on time (left) and with a measurable area under the curve (AUC) (inset).

LC3-II levels were measured in primary cortical neurons following 6 hours of treatment with WHYKD1, WHYKD5, or WHYKD1+BafA1 (FIG. 2). The presence of LC3-II is an indication of autophagy.

LC3-II levels were then measured in organotypic slice cultures following 6 hours of treatment with WHYKD1 (FIG. 3, top panel). Other compounds in the WHYKD series produced similar results (FIG. 3, bottom panel). RFP is a tag on the tau protein and also can be probed.

These experiments show that the WHYKD series of compounds can induce autophagy and reduce the aggregated forms of tau as well as its aggresome surrogate p62.

PLD activation converts phospholipids to phosphatidylethanols in the presence of ethanol. This conversion was measured to show that the WHYKD series of compounds activate PLD at 10 μM concentration (FIG. 4) and at 1 μM (FIG. 5). FIPI is a non-competitive inhibitor of PLD activity and was used as a negative control.

All patents, patent applications, and publications cited above are incorporated herein by reference in their entirety as if recited in full herein.

The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the following claims. 

What is claimed is:
 1. A compound having the formula (II):

wherein Y¹ and Y² are, independently selected from the group consisting of CH and wherein X is selected from the group consisting of H, halide, and aryl; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, hydroxyl-substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 2. The compound of claim 1, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 3. The compound of claim 1, wherein the compound is:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 4. The compound of claim 1, wherein the compound is:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 5. A compound having the formula (III):

wherein Y¹ is CH; wherein Y² is N; wherein X is halide; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 6. The compound of claim 5, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 7. A compound having the formula (IV):

wherein X is halide; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 8. The compound of claim 7, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 9. A compound having the formula (V):

wherein X is H; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 10. The compound of claim 9, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 11. A compound having the formula (VI):

wherein X is H; wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 12. The compound of claim 11, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 13. A compound having the formula (VII):

wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 14. The compound of claim 13, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 15. A compound having the formula (VIII):

wherein R¹ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 16. The compound of claim 15, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 17. A compound having the formula (IX):

wherein Y³ is CH or N; wherein R² is optionally substituted (2-aminoethyl)aryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 18. The compound of claim 17, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 19. A compound having the formula (X):

wherein Y³ is CH; wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 20. The compound of claim 19, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 21. A compound having the formula (XI):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 22. The compound of claim 21, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 23. A compound having the formula (XII):

wherein Y⁴ is CH or N; wherein R³ is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 24. The compound of claim 23, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 25. A compound having the formula (XIII):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 26. The compound of claim 25, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 27. A compound having the formula (XIV):

wherein R² is selected from the group consisting of optionally substituted thioheteroaryl, optionally substituted (2-aminoethyl)aryl, halide, optionally substituted thiocycloalkyl wherein 1-3 carbon atoms of the cycloalkyl is optionally replaced with a heteroatom selected from the group consisting of O, S and N, and thioaryl, or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 28. The compound of claim 27, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 29. A compound having the formula (XV):

wherein X is H or halide; wherein Z¹ is O; wherein R⁴ is selected from the group consisting of H, optionally substituted alkyl, Et, CF₃, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and


30. The compound of claim 29, wherein the compound is selected from the group consisting of:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 31. The compound of claim 29 wherein the compound is:

or a salt, enantiomer, racemate, mixture thereof, or combination thereof.
 32. A pharmaceutical composition comprising a compound of any one of claims 1-31 or a pharmaceutically acceptable salt thereof.
 33. A method of treating a neurodegenerative disease comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-31 or pharmaceutical composition of claim
 32. 34. The method of claim 33, wherein the neurodegenerative disease is a proteinopathy.
 35. The method of claim 34, wherein the proteinopathy is a tauopathy.
 36. The method of claim 33, wherein the neurodegenerative disease is Alzheimer's disease.
 37. A method of enhancing autophagic flux comprising providing to a cell or a protein aggregate an effective amount of a compound of any one of claims 1-31 or pharmaceutical composition of claim
 32. 